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Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution

Author

Listed:
  • Cecilia M Lindgren
  • Iris M Heid
  • Joshua C Randall
  • Claudia Lamina
  • Valgerdur Steinthorsdottir
  • Lu Qi
  • Elizabeth K Speliotes
  • Gudmar Thorleifsson
  • Cristen J Willer
  • Blanca M Herrera
  • Anne U Jackson
  • Noha Lim
  • Paul Scheet
  • Nicole Soranzo
  • Najaf Amin
  • Yurii S Aulchenko
  • John C Chambers
  • Alexander Drong
  • Jian'an Luan
  • Helen N Lyon
  • Fernando Rivadeneira
  • Serena Sanna
  • Nicholas J Timpson
  • M Carola Zillikens
  • Jing Hua Zhao
  • Peter Almgren
  • Stefania Bandinelli
  • Amanda J Bennett
  • Richard N Bergman
  • Lori L Bonnycastle
  • Suzannah J Bumpstead
  • Stephen J Chanock
  • Lynn Cherkas
  • Peter Chines
  • Lachlan Coin
  • Cyrus Cooper
  • Gabriel Crawford
  • Angela Doering
  • Anna Dominiczak
  • Alex S F Doney
  • Shah Ebrahim
  • Paul Elliott
  • Michael R Erdos
  • Karol Estrada
  • Luigi Ferrucci
  • Guido Fischer
  • Nita G Forouhi
  • Christian Gieger
  • Harald Grallert
  • Christopher J Groves
  • Scott Grundy
  • Candace Guiducci
  • David Hadley
  • Anders Hamsten
  • Aki S Havulinna
  • Albert Hofman
  • Rolf Holle
  • John W Holloway
  • Thomas Illig
  • Bo Isomaa
  • Leonie C Jacobs
  • Karen Jameson
  • Pekka Jousilahti
  • Fredrik Karpe
  • Johanna Kuusisto
  • Jaana Laitinen
  • G Mark Lathrop
  • Debbie A Lawlor
  • Massimo Mangino
  • Wendy L McArdle
  • Thomas Meitinger
  • Mario A Morken
  • Andrew P Morris
  • Patricia Munroe
  • Narisu Narisu
  • Anna Nordström
  • Peter Nordström
  • Ben A Oostra
  • Colin N A Palmer
  • Felicity Payne
  • John F Peden
  • Inga Prokopenko
  • Frida Renström
  • Aimo Ruokonen
  • Veikko Salomaa
  • Manjinder S Sandhu
  • Laura J Scott
  • Angelo Scuteri
  • Kaisa Silander
  • Kijoung Song
  • Xin Yuan
  • Heather M Stringham
  • Amy J Swift
  • Tiinamaija Tuomi
  • Manuela Uda
  • Peter Vollenweider
  • Gerard Waeber
  • Chris Wallace
  • G Bragi Walters
  • Michael N Weedon
  • The Wellcome Trust Case Control Consortium
  • Jacqueline C M Witteman
  • Cuilin Zhang
  • Weihua Zhang
  • Mark J Caulfield
  • Francis S Collins
  • George Davey Smith
  • Ian N M Day
  • Paul W Franks
  • Andrew T Hattersley
  • Frank B Hu
  • Marjo-Riitta Jarvelin
  • Augustine Kong
  • Jaspal S Kooner
  • Markku Laakso
  • Edward Lakatta
  • Vincent Mooser
  • Andrew D Morris
  • Leena Peltonen
  • Nilesh J Samani
  • Timothy D Spector
  • David P Strachan
  • Toshiko Tanaka
  • Jaakko Tuomilehto
  • André G Uitterlinden
  • Cornelia M van Duijn
  • Nicholas J Wareham
  • Hugh Watkins for the PROCARDIS consortia
  • Dawn M Waterworth
  • Michael Boehnke
  • Panos Deloukas
  • Leif Groop
  • David J Hunter
  • Unnur Thorsteinsdottir
  • David Schlessinger
  • H-Erich Wichmann
  • Timothy M Frayling
  • Gonçalo R Abecasis
  • Joel N Hirschhorn
  • Ruth J F Loos
  • Kari Stefansson
  • Karen L Mohlke
  • Inês Barroso
  • Mark I McCarthy for the GIANT consortium

Abstract

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10−11) and MSRA (WC, P = 8.9×10−9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10−8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.Author Summary: Here, we describe a meta-analysis of genome-wide association data from 38,580 individuals, followed by large-scale replication (in up to 70,689 individuals) designed to uncover variants influencing anthropometric measures of central obesity and fat distribution, namely waist circumference (WC) and waist–hip ratio (WHR). This work complements parallel efforts that have been successful in defining variants impacting overall adiposity and focuses on the visceral fat accumulation which has particularly strong relationships to metabolic and cardiovascular disease. Our analyses have identified two loci (TFAP2B and MSRA) associated with WC, and a further locus, near LYPLAL1, which shows gender-specific relationships with WHR (all to levels of genome-wide significance). These loci vary in the strength of their associations with overall adiposity, and LYPLAL1 in particular appears to have a specific effect on patterns of fat distribution. All in all, these three loci provide novel insights into human physiology and the development of obesity.

Suggested Citation

  • Cecilia M Lindgren & Iris M Heid & Joshua C Randall & Claudia Lamina & Valgerdur Steinthorsdottir & Lu Qi & Elizabeth K Speliotes & Gudmar Thorleifsson & Cristen J Willer & Blanca M Herrera & Anne U J, 2009. "Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution," PLOS Genetics, Public Library of Science, vol. 5(6), pages 1-13, June.
    • Handle: RePEc:plo:pgen00:1000508
    DOI: 10.1371/journal.pgen.1000508
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    References listed on IDEAS

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    1. Yu-Fang Pei & Jian Li & Lei Zhang & Christopher J Papasian & Hong-Wen Deng, 2008. "Analyses and Comparison of Accuracy of Different Genotype Imputation Methods," PLOS ONE, Public Library of Science, vol. 3(10), pages 1-7, October.
    2. B. Devlin & Kathryn Roeder, 1999. "Genomic Control for Association Studies," Biometrics, The International Biometric Society, vol. 55(4), pages 997-1004, December.
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    Cited by:

    1. Yvonne V Louwers & Nigel W Rayner & Blanca M Herrera & Lisette Stolk & Christopher J Groves & Thomas M Barber & Andre G Uitterlinden & Stephen Franks & Joop S E Laven & Mark I McCarthy, 2014. "BMI-Associated Alleles Do Not Constitute Risk Alleles for Polycystic Ovary Syndrome Independently of BMI: A Case-Control Study," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-7, January.
    2. Zari Dastani & Marie-France Hivert & Nicholas Timpson & John R B Perry & Xin Yuan & Robert A Scott & Peter Henneman & Iris M Heid & Jorge R Kizer & Leo-Pekka Lyytikäinen & Christian Fuchsberger & Tosh, 2012. "Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals," PLOS Genetics, Public Library of Science, vol. 8(3), pages 1-23, March.
    3. Dorthe S Bille & Karina Banasik & Johanne M Justesen & Camilla H Sandholt & Annelli Sandbæk & Torsten Lauritzen & Torben Jørgensen & Daniel R Witte & Jens-Christian Holm & Torben Hansen & Oluf Pederse, 2011. "Implications of Central Obesity-Related Variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on Quantitative Metabolic Traits in Adult Danes," PLOS ONE, Public Library of Science, vol. 6(6), pages 1-7, June.
    4. Nicole M Warrington & Yan Yan Wu & Craig E Pennell & Julie A Marsh & Lawrence J Beilin & Lyle J Palmer & Stephen J Lye & Laurent Briollais, 2013. "Modelling BMI Trajectories in Children for Genetic Association Studies," PLOS ONE, Public Library of Science, vol. 8(1), pages 1-12, January.
    5. Joshua C Randall & Thomas W Winkler & Zoltán Kutalik & Sonja I Berndt & Anne U Jackson & Keri L Monda & Tuomas O Kilpeläinen & Tõnu Esko & Reedik Mägi & Shengxu Li & Tsegaselassie Workalemahu & Mary F, 2013. "Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits," PLOS Genetics, Public Library of Science, vol. 9(6), pages 1-19, June.

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